Doublecortin (DCX) is a key regulator of neuronal migration in the cerebral cortex. Defects of DCX protein function result in double cortex/X-linked lissencephaly syndrome, an X-linked brain malformation resulting from aberrant migration of neurons during development of the cerebral cortex, severely affecting males over females. Targeted therapeutics are unavailable to date as the molecular mechanisms underlying this rare disorder are presently not understood. Recent data show that DCX is required during neuronal development for selective transport of synaptic vesicle precursors along microtubules (MTs) by the neuron-specific kinesin-3 motor KIF1A. DCX, which defines a class of microtubule-associated proteins (MAPs) with conserved microtubule binding domains, selectively facilitates binding of the KIF1A motor domain to the MT, most likely through regulation of motor dynamics during processive movement of the motor along the MT. The objective of this proposal is to develop a working model of the interactions of DCX, KIF1A, and the MT within the context of the live cell. Through these studies we will gain general insight into the basic mechanisms governing MT-based molecular motor transport during early neuronal development. The specific aims of this study are to: 1) Develop a model for DCX-dependent KIF1A-mediated vesicle transport within a cellular context;and 2) Develop a MAP-kinesin "code" for vesicular transport during human brain development. The insights obtained from these studies will facilitate the design and development of novel mechanism-based therapeutic strategies for the treatment of a variety of neurodevelopmental disorders caused by structural and/or functional failure of DCX domain proteins. PUBLIC HEALTH RELEVANCE: Doublecortin (DCX) domain proteins are a family of microtubule-associated proteins (MAPs) whose specific cellular functions are not well understood, but recent data suggests a potential role in regulating kinesin- mediated vesicle transport during early brain development. This proposal aims at developing a working model of DCX-dependent kinesin function within the context of the live cell, and determining the specificity of DCX domain proteins and other MAPs for molecular motors. Such basic biological insight will allow the design and development of novel mechanism-based therapeutic strategies for the treatment of a variety of neurodevelopmental disorders caused by structural and/or functional failure of DCX domain proteins.